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Updated: Jan 10, 2026

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Nuclear Alpha-Synuclein: Mechanisms and Implications for Synucleinopathies.

Tiago Fleming Outeiro1,2, David J Koss3

  • 1Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.

Movement Disorders : Official Journal of the Movement Disorder Society
|November 26, 2025
PubMed
Summary

Alpha-synuclein protein moves into neuronal nuclei, impacting DNA and aging, potentially driving Parkinson's disease. Targeting nuclear alpha-synuclein offers new therapeutic and biomarker strategies for synucleinopathies.

Keywords:
DNA damageParkinson's diseasealpha‐synucleinneurodegenerationprotein aggregation

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Alpha-synuclein (aSyn) is known for synaptic roles and Lewy bodies in Parkinson's disease (PD).
  • Emerging evidence highlights aSyn's nuclear functions relevant to neurodegeneration.
  • Nuclear aSyn's role in genomic stability and DNA repair is under investigation.

Purpose of the Study:

  • To explore the nuclear activities of alpha-synuclein in health and disease.
  • To investigate the mechanisms by which nuclear aSyn contributes to neurodegeneration.
  • To assess the potential of nuclear aSyn as a biomarker and therapeutic target for synucleinopathies.

Main Methods:

  • Utilized experimental models to study nuclear aSyn localization and function.
  • Investigated aSyn interactions with chromatin, DNA, and DNA repair machinery.
  • Employed advanced immunohistochemical and molecular techniques for detection in human tissues.

Main Results:

  • Nuclear aSyn dynamically localizes to neurons in both healthy and diseased states.
  • Nuclear aSyn, particularly phosphorylated or oligomeric forms, promotes neurodegeneration.
  • Dysregulation of transcription, DNA repair deficits, and cellular senescence are linked to nuclear aSyn.

Conclusions:

  • Nuclear aSyn plays a critical role in the pathogenesis of Parkinson's disease and related disorders.
  • Nuclear aSyn represents a potential biomarker for disease stratification.
  • Targeting nuclear aSyn pathways offers novel therapeutic strategies for synucleinopathies.